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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Hematology, University of
Cambridge, Cambridge, United Kingdom; Victorian Cancer Cytogenetic
Service, St Vincent Hospital, Fitzroy, Australia; Oncology Cytogenetics
Service, Christie Hospital, Manchester, United Kingdom; Department of
Hematology, Western General Hospital, Edinburgh, United Kingdom;
Department of Clinical Hematology and Medical Oncology, Royal
Melbourne Hospital, Melbourne, Australia;Department of Hematology,
Peter Macallum Cancer Institute, Melbourne, Australia;Department of
Hematology, Alfred Hospital, Melbourne, Australia; and Digital
Scientific, Cambridge, United Kingdom.
Chronic myeloid leukemia (CML) is characterized by formation of the
BCR-ABL fusion gene, usually as a consequence of the
Philadelphia (Ph) translocation between chromosomes 9 and 22. Large
deletions on the derivative chromosome 9 have recently been reported,
but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ
hybridization (FISH) analysis was used to assess the deletion status of
253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease
progression but was significantly increased in patients with variant Ph
translocations. In patients with a deletion, all Ph+
metaphases carried the deletion. The median survival of patients with
and without deletions was 38 months and 88 months, respectively (P = .0001). By contrast the survival difference between
Sokal or Hasford high-risk and non-high-risk patients was of only
borderline significance (P = .057 and
P = .034). The results indicate that deletions occur at
the time of the Ph translocation. An apparently simple reciprocal
translocation may therefore result in considerable genetic
heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status
is also a powerful and independent prognostic factor for patients with
CML. The prognostic significance of deletion status should now be
studied prospectively and, if confirmed, should be incorporated into
management decisions and the analysis of clinical trials.
(Blood. 2001;98:1732-1738) Chronic myeloid leukemia (CML) is a clonal
hematologic malignancy that results from transformation of a
multipotent hemopoietic stem cell.1-3 The molecular
hallmark of CML is the formation of a BCR-ABL fusion gene,
usually formed as a consequence of the Philadelphia (Ph) translocation
involving chromosomes 9 and 22.4-6 BCR-ABL
plays a pivotal role in the pathogenesis of CML and its formation is
likely to represent the initiating event. In support of this concept
transgenic and retroviral transduction studies have demonstrated that
expression of BCR-ABL in murine bone marrow cells resulted
in leukemia, with some cases closely resembling CML.7-13
In one recent transgenic model the leukemia could be reversed by
down-regulating BCR-ABL.14
Chronic myeloid leukemia is a biphasic disease with an initial chronic
phase that is readily controlled. However, this is followed by an
ill-defined accelerated phase, and then a terminal blastic phase that
resembles an acute leukemia, which is usually refractory to therapy.
Transformation to blast crisis is accompanied by secondary cytogenetic
changes in about 85% of cases,15 but the molecular basis
for this transformation is poorly understood. A number of molecular
changes have been identified in a minority of cases of blast crisis,
including mutations or deletions of p53,
p16INKA, and the retinoblastoma protein, and
mutation or overexpression of Ras and
EVI-1.1,2 However, none provide a method for
prospectively distinguishing those patients who will progress rapidly
to blast crisis from those patients whose disease pursues an indolent course.
Treatment options for patients with chronic phase CML currently include
hydroxyurea, interferon We and others have recently reported previously unrecognized deletions
adjacent to the t(9;22) breakpoint on the derivative chromosome
9.22-25 The deletions were large, spanning up to several megabases, displayed variable breakpoints, and usually resulted in
genomic loss of sequences from both the chromosome 9 and chromosome 22 sides of the translocation breakpoint.25 However, it was not clear whether the deletions arose during disease
progression,22 as a consequence of genomic
instability,26,27 or alternatively whether they occurred
at the time of the original Ph translocation.25 Moreover,
although it was reported that the deletions may be associated with a
more rapid onset of blast crisis, the number of patients studied was
small and the survival difference complicated by the fact that few
patients with deletions had received IFN- Patient samples and clinical and laboratory data
Fluorescent in situ probes and detection systems
Triple-probe/3-color system.
This system (Figure 1) was used as
described.29 Briefly, it uses 3 probes, each labeled with
a separately colored fluorochrome. These are: (1) ASS probe, a 350-kb
cosmid contig that contains the ASS and 8604 Met genes, both mapping proximal to the first exon of ABL
and labeled with Spectrum Aqua; (2) ABL probe (Vysis, Downers Grove,
IL), a 300-kb cosmid contig that contains the 3' region of the
ABL gene (exons 3-11), labeled with Spectrum Orange; and (3)
BCR probe (Vysis), an approximately 300-kb contig that begins between
exons 13 and 14 of BCR and extends well beyond the M-bcr
region, labeled with Spectrum Green.
Dual-fluorescent in situ hybridization BCR-ABL detection system.
This system (Figure 1) was used according to the manufacturer's
instructions (Qbiogene, Middlesex, United Kingdom). It uses 2 probes: (1) ABL probe, a 600-kb contig spanning the breakpoint region
on ABL labeled with fluorescein isothiocyanate (FITC) and (2) BCR, a
500-kb contig containing the major and minor breakpoint regions of BCR
labeled with Texas red.
Digital imaging and analysis
Statistical analysis All calculations were performed with the SPSS statistical package (SPSS, Chicago IL). Medians and interquartile ranges were calculated for age and clinical and laboratory findings at diagnosis for patients with and without deletions (Table 1) and tested for any significant differences with the Mann-Whitney U test (for continuous variables) or 2 analysis and Fisher exact tests (for
categorical variables). Survival time was calculated from month of
presentation to month of death, with a median follow-up of 34 months
(range, 1-117 months). Patients who died in chronic phase for reasons
unrelated to CML and bone marrow transplant recipients were censored at
the time of death and transplantation, respectively. Survival data were calculated with the Kaplan-Meier estimator and significance was assessed with the log-rank test. The analysis was performed both by
time censoring at the time of transplantation or death due to causes
unrelated to CML and also by excluding these patients from analysis.
Patient age, sex, platelet count, percentage of peripheral blood
blasts, classical or variant translocation, and initial Hasford and
Sokal scores were considered potentially confounding prognostic
factors. The respective P values for the univariate analyses
were age (P = .002), sex (P = .44),
percentage peripheral blood blasts (P = .001), platelets
(P = .1), classical/variant translocation
(P = .14), initial Sokal group (P = .04), and
initial Hasford group (P = .08). Univariate analysis was
performed for these variables and those significant at the P
less than .2 level were included in a multivariate analysis from
which a forward stepping procedure was used to derive the most
significant model. The hazard ratio of deletion status as a univariate
analysis was then compared to the hazard ratios following adjustment
for initial Hasford and Sokal scores and to the hazard ratio for the
most significant model.
Bone marrow samples from 253 patients with CML were studied using the triple-probe29 and dual-FISH (D-FISH) systems.30 Figure 1 shows the hybridization patterns expected in "normal" Ph+ cells and in Ph+ cells carrying a deletion of the derivative chromosome 9. Deletions were detected in 39 of 253 patients (15%) of whom 30 demonstrated deletion of both chromosome 9 and 22 sequences. Deletions of only chromosome 9 sequences were detected in 7 patients, with deletion of only chromosome 22 sequences detected in 2 patients. There was complete concordance between the triple-probe and D-FISH analyses. Deletions occur at the time of the Ph translocation Deletions of the derivative chromosome 9 may reflect genomic instability during disease progression or may arise at the time of the initial Ph translocation. We have investigated this issue in several ways. First, patients analyzed in different phases of the disease were found to exhibit virtually identical frequencies of deletions. In the whole cohort, 15% (39 of 253) of samples carried a deletion. In samples taken at diagnosis, 14% (22 of 160) carried a deletion compared to 16% (10 of 64) of samples taken following progression to accelerated phase or blast crisis (2,
P = .72). Sequential paired samples were also analyzed,
with the second sample taken following disease progression. In 34 of 37 patients the initial chronic phase sample lacked a deletion. In these
34 patients none of 1306 Ph+ metaphases obtained after
disease progression (30 blast crisis, 4 accelerated phase) had acquired
a deletion.
Second, deletions were observed in 16 of 41 (39%) patients with a
variant translocation compared to 25 of 212 (11%) patients with a
classical Ph translocation ( Third, if deletions occurred during disease progression it should be possible to identify cells carrying the Ph translocation but no deletion. We therefore analyzed a total of 1524 metaphases from the 39 patients shown to carry a deletion. In every metaphase both a Ph translocation and a deletion were demonstrated. Taken together these data demonstrate that the recombination event producing an apparently reciprocal translocation also results in large genomic deletions. This process gives rise to previously unsuspected genetic heterogeneity and is likely to be widely applicable to other malignancies associated with translocations. Deletion status is a powerful prognostic indicator in CML Survival data were available from 241 patients (39 with and 202 without a deletion). The clinical and laboratory characteristics of patients with and without deletions are shown in Table 1 and are similar for both. However, Kaplan-Meier analysis revealed a striking difference in survival (Figure 2). The estimated median survival time for patients with deletions was 38 months (95% CI [confidence interval], 36.5-39.4) compared to 88 months (95% CI, 64-111) for patients without deletions, with a similar median follow-up time for each group (31 versus 34 months, respectively). This difference in survival time was highly significant by log-rank analysis (P = .0001; Figure 2). Exclusion of patients who received an allogeneic stem cell transplant (n = 75) or were censored due to death unrelated to CML (n = 6) resulted in an increase in the level of significance (log-rank, P < .0001). This survival difference remained highly significant when the 55 previously reported patients were excluded from the analysis (estimated median survival 81 months for patients without deletions versus 53 months for patients with deletions, P = .007). Hazard ratios for patients with deletions compared to those without are shown in Table 2. These were calculated for deletion status alone, for deletion status after correction for initial Hasford and Sokal scores, and for deletion status following correction for initial blast count and age, the only 2 variables to provide additional prognostic value in the multivariate model constructed. The hazard ratios are all very similar, ranging from 3.0 to 3.2, indicating the independence of deletion status as a prognostic factor.
Multivariate analysis using a forward stepping model showed the
prognostic importance of deletion status remained after adjusting for
age, sex, percentage of peripheral blood blasts, platelet count, and
initial Sokal and Hasford scores (Table 2). Two potentially confounding
variables were further investigated. First, fewer patients with a
deletion had received treatment with IFN- The prognostic strength of deletion status, Sokal score, and Hasford
score were then compared in 210 patients for whom all the necessary
clinical information was available. As shown in Table
3 and Figure 2, Sokal and Hasford
high-risk groups had estimated median survivals of 56 and 55 months,
respectively, compared to 37 months for patients with deletions.
Moreover, in contrast to the striking prognostic significance of
deletion status (P = .0001), the survival difference
between high-risk and non-high-risk (low plus intermediate risk)
patients using either the Sokal or Hasford scoring systems was only of
borderline significance (P = .058 and
P = .034, respectively). Because the Hasford score was
developed specifically for patients treated with IFN-
Deletion status identified a smaller proportion of patients as being high risk (15%) compared to the Sokal or Hasford scoring systems (37% and 22%, respectively; Table 3). However, patients with deletions were not merely a subset of the Sokal and Hasford high-risk groups because, within this cohort of 210 patients, similar numbers of patients with deletions were found in Sokal and Hasford low-, intermediate-, and high-risk groups. There were 11 of 78 (14%), 9 of 67 (13%), and 12 of 65 (18%) patients, respectively, in the Sokal low-, intermediate-, and high-risk groups and 10 of 80 (13%), 15 of 84 (18%), and 7 of 46 (15%) patients in the 3 respective Hasford risk groups. These results agree well with our findings that the hazard ratios associated with deletion status remain virtually unchanged following adjustment for Sokal or Hasford score, implying independence of deletion status as a prognostic factor (Table 2 and above). Consistent with this concept, the Sokal and Hasford scoring systems retain prognostic significance if analysis is restricted to patients without a deletion (Sokal high-risk versus non-high-risk P = .03; Hasford high-risk versus non-high-risk P = .04). The striking prognostic power of deletion status relative to the Sokal and Hasford systems is likely to reflect the fact that deletion status directly detects a molecular event with a critical role in the progression of CML.
Patients with CML display considerable clinical heterogeneity during the chronic phase of the disease, with some individuals progressing rapidly to blast crisis and death, whereas others remain well controlled for many years. The molecular basis for this variability remains obscure. Here we demonstrate that the Ph translocation event itself can give rise to considerable genetic heterogeneity in the form of large deletions of sequences on the derivative chromosome 9. These results show that the pathogenetic consequences of an apparently "simple" translocation may frequently be more complex than previously realized, a concept that is likely to apply to other malignancies with chromosomal translocations. It has previously been suggested that deletions of the derivative
chromosome 9 may be associated with a worse survival.25 However, the number of patients studied was small (55 in total and only
16 of whom had deletions). There was also a much higher proportion of
variant Ph translocations (21 of 55, 38%) within this cohort than
occur randomly. Moreover, the significance of the survival difference
was complicated by the fact that few patients with deletions had
received IFN- Our data also provide an explanation for conflicting previous reports of the prognostic significance of variant Ph translocations.32,33,39,40 Patients with a variant Ph translocation have a more than 3-fold increase in the frequency of deletions, although patients with a deletion still represent a minority (39%) of patients with a variant Ph translocation. Differences in the proportion of patients carrying a deletion are therefore likely to account for previous controversy concerning the prognostic significance of variant compared to classical Ph translocations. What might be the molecular mechanism whereby deletions confer such a poor prognosis? Several models can be envisaged. First, deletions will result in loss of the reciprocal fusion gene, ABL-BCR. However, current evidence suggests that this is unlikely to be the critical event because no ABL-BCR protein has been detected41 and ABL-BCR expression does not correlate with prognosis as assessed by cytogenetic response.42 Second, a deletion on the derivative chromosome 9 may act as a surrogate marker for smaller intronic deletions on the Ph chromosome, which may influence the level of BCR-ABL expression. Blast crisis is sometimes associated with the acquisition of an additional Ph chromosome suggesting that BCR-ABL dosage may be important. A third potential mechanism would involve the loss of one or more genes
within the deleted region. Such loss may be sufficient to produce a
neoplastic effect (haploinsufficiency) or may require subsequent
inactivation of the corresponding normal allele(s).43 The
deletions are large, extending up to 5.5 Mb on the chromosome 9 side of
the translocation breakpoint and up to 17 Mb on the chromosome 22 side
of the breakpoint (Sinclair et al25 and B.J.P.H., unpublished data, April, 2001). Both of these regions are gene rich. The chromosome 9 region contains 44 known genes and another 40 predicted genes and the chromosome 22 region contains 138 known genes
and a further 91 predicted genes based on genome sequence analysis.44 The chromosome 22 region contains 3 known tumor suppressor genes, the chromatin remodeling gene
hSNF5/INI1,45 the neurofibromatosis type 2 gene
NF2,46 and MN1/MGCR1-PEN, a putative
tumor suppressor gene associated with sporadic meningioma and
rearranged in a myeloproliferative disorder with
t(12;22).47 Both the chromosome 9 and chromosome 22 regions contain a number of other genes encoding transcription
factors/cofactors (PBX3,48 LMX1B
49), components of signal transduction pathways (the
serine/threonine phosphatase PP2A,50 Ras
inhibitor INF,51 lim domain protein kinase
LIM-K2,52 GM-CSF/IL-3/IL-5
receptor common chain Finally, deletions may represent a consequence of genetic instability within the target cell at the time of the Ph translocation. In this case the poor prognosis would reflect a predisposition to subsequent additional genetic alterations within the malignant clone. Patients with chronic phase CML do not exhibit genomic instability as assessed by microsatellite analysis,55,56 but these data do not exclude more subtle levels of genetic instability. It is also worth emphasizing that further layers of complexity may exist because the 4 mechanisms discussed above are not mutually exclusive.
We are grateful to Eleanor Pinto, Toby Prevost, and Sue Richards for statistical advice and to the Adult Leukemia Working Party of the Medical Research Council of the United Kingdom for providing 48 patients for the study.
Submitted February 28, 2001; accepted May 15, 2001.
B.J.P.H. is a Medical Research Council (United Kingdom) Clinical Training Fellow. Work in the authors' laboratories is supported by the Leukemia Research Fund and the Kay Kendall Leukemia Fund.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Anthony R. Green, Department of Hematology, University of Cambridge, Wellcome Trust/MRC Building, Hills Rd, Cambridge, CB2 2XY, United Kingdom; e-mail: arg1000{at}cam.ac.uk.
1. Faderl S, Talpaz M, Estrav Z, O'Brien S, Kuzrock R, Kantarjian H. The biology of chronic myeloid leakemia. N Engl J Med. 1999;341:167-172.
2.
Deininger M, Goldman J, Melo J.
The molecular biology of chronic myeloid leukemia.
Blood
2000;96:3343-3356
3.
Sawyers C.
Chronic myeloid leukemia.
N Engl J Med.
1999;340:1330-1340 4. Bartram C, de Klein A, Hagemeijer A. Translocation of c-abl oncogene correlates with the presence of the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277-280[CrossRef][Medline] [Order article via Infotrieve]. 5. Groffen J, Stephenson J, Heisterkamp N, de Klein A, Bartram C, Grosveld G. Philadelphia chromosome breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984;36:93-99[CrossRef][Medline] [Order article via Infotrieve]. 6. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-293[CrossRef][Medline] [Order article via Infotrieve].
7.
Daley G, Van Etten R, Baltimore D.
Induction of chronic myelogenous leukemia in mice by the p210bcr/abl gene of the Philadelphia chromosome.
Science.
1990;247:824-830 8. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale P, Goffen J. Acute leukemia in bcr-abl transgenic mice. Nature. 1990;344:251-253[CrossRef][Medline] [Order article via Infotrieve]. 9. Elefanty A, Hariharan I, Cory S. BCR-ABL, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 1990;9:1069-1078[Medline] [Order article via Infotrieve].
10.
Voncken J, Kaartinen V, Pattengale P, Germeraad W, Groffen J, Heisterkamp N.
BCR/ABL p210 and p190 cause distinct leukemia in transgenic mice.
Blood.
1995;86:4603-4611
11.
Zhang X, Ren R.
Bcr-abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukaemia.
Blood.
1998;92:3829-3840
12.
Pear W, Miller J, Xu L, et al.
Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving p210 bcr/abl transduced bone marrow.
Blood.
1998;92:3780-3792
13.
Honda H, Oda H, Takahiro S, et al.
Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias.
Blood.
1998;91:2067-2075 14. Huettner C, Zhang P, Van Etten R, Tenen D. Reversibility of acute B-cell leukemia induced by BCR-ABL1. Nat. Genet. 2000;24:57-60[CrossRef][Medline] [Order article via Infotrieve]. 15. Bernstein R. Cytogenetics of chronic myelogenous leukemia. Semin Hematol. 1988;25:20-34[Medline] [Order article via Infotrieve].
16.
Druker B, Sawyers C, Kantarjian H, et al.
Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukaemia with the Philadelphia chromosome.
N Engl J Med.
2001;344:1038-1042
17.
Druker B, Talpaz M, Resta D, et al.
Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukaemia.
N Engl J Med.
2001;344:1031-1037
18.
Peters D, Hoover R, Gertach M, et al.
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukaemia and primary cells from patients with chronic myeloid leukaemia.
Blood.
2001;97:1404-1411
19.
Reichert A, Heisterkamp N, Daley G, Groffen J.
Treatment of Bcr/Abl-positive acute lymphoblastic leukaemia in P190 mice with the farnesyl transferase inhibitor SCH66336.
Blood.
2001;97:1399-1403 20. Sokal J, Cox E, Baccarini M. Prognostic discrimination in "good risk" chronic granulocytic leukemia. Blood. 1984;63:1352-1357.
21.
Hasford J, Pfirrmann M, Hehlmann R, et al.
A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alpha.
J Natl Cancer Inst.
1998;90:850-858
22.
Grand F, Kulkarni S, Chase A, Goldman JM, Cross NCP.
Frequent deletion of hSNF5/INI1, a component of the SWI/SNF complex, in chronic myeloid leukaemia.
Cancer Res.
1999;59:3870-3874 23. Dewald G, Wyatt W, Silver R. Atypical BCR and ABL D-FISH patterns in chronic myeloid leukemia and their possible role in therapy. Leuk Lymphoma. 1999;34:481-491[Medline] [Order article via Infotrieve]. 24. Herens C, Tassin F, Lemaire V, et al. Deletion of the 5'-ABL region: a recurrent anomaly detected by fluorescence in situ hybridisation in about 10% of Philadelphia-positive chronic myeloid leukaemia patients. Br J Haematol. 2000;110:214-216[CrossRef][Medline] [Order article via Infotrieve].
25.
Sinclair PB, Nacheva EP, Laversha M, et al.
Large deletions at the t(9; 22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukaemia.
Blood.
2000;95:738-744
26.
Takeda N, Shibuya M, Maru Y.
The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein.
Proc Natl Acad Sci U S A.
1999;96:203-207 27. Canitrot Y, Lautier D, Laurent G, et al. Mutator phenotype of BCR-ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase beta. Oncogene. 1999;18:2676-2680[CrossRef][Medline] [Order article via Infotrieve]. 28. Allan N, Richards S, Shepherd P, et al. UK Medical Research Council randomised multicentre trial of interferon-alpha for chronic myeloid leukemia: improved survival irrespective of cytogenetic response. Lancet. 1995;345:1392-1397[CrossRef][Medline] [Order article via Infotrieve].
29.
Sinclair P, Green A, Grace C, Nacheva E.
Improved sensitivity of BCR-ABL detection: a triple probe three-color fluorescence in situ hybridization system.
Blood.
1997;90:1395-1402
30.
Dewald G, Wyatt W, Juneau A, et al.
Highly sensitive fluorescence in situ hybridization method to detect double BCR/ABL fusion and monitor response to therapy in chronic myeloid leukemia.
Blood.
1998;91:3357-3365 31. Calabrese G, L S, Franchi P, et al. Complex translocations of the Ph chromosome and Ph negative CML arise from similar mechanisms, as evidenced by FISH analysis. Cancer Genet Cytogenet. 1994;78:153-159[CrossRef][Medline] [Order article via Infotrieve]. 32. Potter A, Watmore A, Cooke P, Lilleyman J, Sokol R. Significance of non-standard Philadelphia chromosomes in chronic granulocytic leukaemia. Br J Cancer. 1981;44:51-54[Medline] [Order article via Infotrieve]. 33. Bernstein R, Pinto M, Wallace C, Penfold G, Mendelow B. The incidence, type and subsequent evolution of 14 variant Ph1 translocations in 180 South African patients with Ph1 chronic myeloid leukemia. Cancer Genet Cytogenet. 1984;12:225-228[CrossRef][Medline] [Order article via Infotrieve]. 34. Gratwohl A, Hermans J, Goldman J, et al. Risk assessment for patients with chronic myeloid leukaemia before allogenic blood or bone marrow transplantation. Lancet. 1998;352:1087-1092[CrossRef][Medline] [Order article via Infotrieve].
35.
The Italian Cooperative Study Group on Chronic Myeloid Leukemia.
Interferon-alpha 2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia.
N Engl J Med.
1994;330:820-825
36.
Guiholt F, Chastang C, Michalet M, Geurci A, Harouseau J-L, Maloisel F.
Interferon alfa 2b combined with cytarabine versus interferon alpha alone in chronic myelogenous leukemia.
N Engl J Med.
1997;337:223-229 37. Hehlmann R. Trial of IFN or STI 571 before proceeding to allografting for CML. Leukemia. 2000;14:1560-1562[CrossRef][Medline] [Order article via Infotrieve]. 38. Tura S, Kantarjian H, Melo J, Giralt S, Talpaz M. Chronic myelogenous leukemia: disease biology and current and future therapeutic strategies. In: Schectner G,Berliner N,Telen M, eds. Hematology 2000. San Francisco: American Society of Hematology; 2000:90-109. 39. Sandberg A. Chromosomes and causation of human cancer and leukemia: the Ph1 and other translocations in CML. Cancer. 1980;46:2221-2226[CrossRef][Medline] [Order article via Infotrieve]. 40. De Braekleer M. Variant translocations in chronic myeloid leukemia. Cytogenet Cell Genet. 1987;44:215-222[Medline] [Order article via Infotrieve]. 41. Melo J. BCR-ABL gene variants. In: Goldman J, ed. Chronic Myeloid Leukaemia. London, United Kingdom: Baillière Tindall; 1997:203-222.
42.
Melo J, Hochhaus A, Yan X-H, Goldman J.
Lack of correlation between ABL-BCR expression and response to interferon- 43. Asimakopoulos FA, Green AR. Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders. Br J Haematol. 1996;95:219-226[CrossRef][Medline] [Order article via Infotrieve]. 44. Birney E, Bateman A, Clamp M, Hubbard T. Mining the draft human genome. Nature. 2001;409:827-828[CrossRef][Medline] [Order article via Infotrieve]. 45. Versteege I, Sevent N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394:203-206[CrossRef][Medline] [Order article via Infotrieve]. 46. Ruttledge M, Sarrazin J, Rangaratnam S, et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet. 1994;6:180-184[CrossRef][Medline] [Order article via Infotrieve]. 47. Buijs A, Sherr S, van Baal S, et al. Translocation (12;22)(p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene. 1995;10:1511-1519[Medline] [Order article via Infotrieve].
48.
Monica K, Galili N, Nourse J, Saltman D, Cleary M.
PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.
Mol Cell Biol
1991;11:6149-6157 49. Dreyer S, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998;19:47-50[CrossRef][Medline] [Order article via Infotrieve]. 50. Millward T, Zolnierowicz S, Hemmings B. Regulation of the protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999;24:186-191[CrossRef][Medline] [Order article via Infotrieve].
51.
Colicelli J, Nicolette C, Birchmeier C, Rodgers L, Riggs M, Wigler M.
Expression of three mammalian cDNAs that interfere with RAS fuction in Saccharomyces cerevisiae.
Proc Natl Acad Sci U S A.
1991;88:2913-2917
52.
Maekawa M, Ishizaki T, Boku S, et al.
Signalling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.
Science.
1999;285:895-898
53.
Dirksen U, Hattenhorst U, Schneider P, et al.
Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common
54.
Grana X, De Luca A, Sang N, et al.
PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro.
Proc Natl Acad Sci U S A.
1994;91:3834-3838
55.
Wada C, Shionoya S, Fujino Y, et al.
Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia.
Blood.
1994;83:3449-3456 56. Silly H, Chase A, Mills K, et al. No evidence for microsatellite instability or consistent loss of heterozygosity at selected loci in chronic myeloid leukaemia blast crisis. Leukemia. 1994;8:1923-1928[Medline] [Order article via Infotrieve].
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  H. Kantarjian, C. Schiffer, D. Jones, and J. Cortes Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods Blood, February 15, 2008; 111(4): 1774 - 1780. [Full Text] [PDF]
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 G. Strathdee, T. L. Holyoake, A. Sim, A. Parker, D. G. Oscier, J. V. Melo, S. Meyer, T. Eden, A. M. Dickinson, J. C. Mountford, et al. Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis Clin. Cancer Res., September 1, 2007; 13(17): 5048 - 5055. [Abstract] [Full Text] [PDF]
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S. Kreil, M. Pfirrmann, C. Haferlach, K. Waghorn, A. Chase, R. Hehlmann, A. Reiter, A. Hochhaus, N. C. P. Cross, and for the German Chronic Myelogenous Leukemia (CML) Heterogeneous prognostic impact of derivative chromosome 9 deletions in chronic myelogenous leukemia Blood, August 15, 2007; 110(4): 1283 - 1290. [Abstract] [Full Text] [PDF]
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 S. Perner, F. Demichelis, R. Beroukhim, F. H. Schmidt, J.-M. Mosquera, S. Setlur, J. Tchinda, S. A. Tomlins, M. D. Hofer, K. G. Pienta, et al. TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer. Cancer Res., September 1, 2006; 66(17): 8337 - 8341. [Abstract] [Full Text] [PDF]
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A. Quintas-Cardama, H. Kantarjian, M. Talpaz, S. O'Brien, G. Garcia-Manero, S. Verstovsek, M. B. Rios, K. Hayes, A. Glassman, B. N. Bekele, et al. Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia Blood, March 15, 2005; 105(6): 2281 - 2286. [Abstract] [Full Text] [PDF]
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 J. M. Goldman and J. V. Melo Chronic Myeloid Leukemia -- Advances in Biology and New Approaches to Treatment N. Engl. J. Med., October 9, 2003; 349(15): 1451 - 1464. [Full Text] [PDF]
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B. J. P. Huntly, F. Guilhot, A. G. Reid, G. Vassiliou, E. Hennig, C. Franke, J. Byrne, A. Brizard, D. Niederwieser, J. Freeman-Edward, et al. Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions Blood, September 15, 2003; 102(6): 2205 - 2212. [Abstract] [Full Text] [PDF]
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B. J. P. Huntly, A. Bench, and A. R. Green Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia Blood, August 15, 2003; 102(4): 1160 - 1168. [Abstract] [Full Text] [PDF]
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 T S K Wan, S K Ma, W Y Au, and L C Chan Derivative chromosome 9 deletions in chronic myeloid leukaemia: interpretation of atypical D-FISH pattern J. Clin. Pathol., June 1, 2003; 56(6): 471 - 474. [Abstract] [Full Text] [PDF]
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 J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF]
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A. F. List, K. J. Kopecky, C. L. Willman, D. R. Head, M. L. Slovak, D. Douer, S. R. Dakhil, and F. R. Appelbaum Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase Blood, August 13, 2002; 100(5): 1910 - 1912. [Abstract] [Full Text] [PDF]
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 G. Saglio, C. T. Storlazzi, E. Giugliano, C. Surace, L. Anelli, G. Rege-Cambrin, A. Zagaria, A. J. Velasco, A. Heiniger, P. Scaravaglio, et al. A 76-kb duplicon maps close to the BCR gene on chromosome 22 and the ABL gene on chromosome 9: Possible involvement in the genesis of the Philadelphia chromosome translocation PNAS, July 23, 2002; 99(15): 9882 - 9887. [Abstract] [Full Text] [PDF]
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B. J. P. Huntly, A. J. Bench, E. Delabesse, A. G. Reid, J. Li, M. A. Scott, L. Campbell, J. Byrne, E. Pinto, A. Brizard, et al. Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCR expression, elevated BCR-ABL levels, or karyotypic instability Blood, May 29, 2002; 99(12): 4547 - 4553. [Abstract] [Full Text] [PDF]
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A. G. Reid, B. J. P. Huntly, E. Hennig, D. Niederwieser, L. J. Campbell, N. Bown, N. Telford, H. Walker, C. D. Grace, M. W. Deininger, et al. Deletions of the derivative chromosome 9 do not account for the poor prognosis associated with Philadelphia-positive acute lymphoblastic leukemia Blood, March 15, 2002; 99(6): 2274 - 2275. [Full Text] [PDF]
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J. de la Fuente, K. Merx, E. J. Steer, M. Muller, R. M. Szydlo, O. Maywald, U. Berger, R. Hehlmann, J. M. Goldman, N. C. P. Cross, et al. ABL-BCR expression does not correlate with deletions on the derivative chromosome 9 or survival in chronic myeloid leukemia Blood, November 1, 2001; 98(9): 2879 - 2880. [Full Text] [PDF]
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B. J. Druker, C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman Chronic Myelogenous Leukemia Hematology, January 1, 2001; 2001(1): 87 - 112. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
(IFN-
